A better understanding of lung development will have a broad and significant impact on perinatal health and facilitate efforts to direct the differentiaion of pulmonary tissue from human stem cells. Embryonic lung development is regulated by a series of epithelial-mesenchymal interactions. Two signaling pathways have been implicated in the specification of Nxk2.1-expressing lung progenitors from the foregut epithelium; FGFs and Wnt2/2b. After pulmonary specification further crosstalk between Wnt, FGF, Shh, TGF-, BMP and RA pathways regulate lung bud growth, differentiation and morphogenesis. Despite recent progress a number of critical unanswered questions remain. First, the molecular pathways upstream of Wnt2/2b are undefined. It is unclear if early FGF and Wnt2/2b act in an epistatic pathway and their target genes are largely unknown. Finally the relationship between FGF/Wnt-mediated lung specification and the pathways regulating lung bud growth are poorly understood. Our preliminary data support the hypothesis that the Odd skipped related (Osr) zinc finger transcription factors are key components of an epithelial-mesenchymal signaling cascade linking early foregut patterning by FGFs to Wnt-mediated pulmonary specification and RA-regulated lung bud growth into a unified molecular pathway. This proposal, which uses an innovative multi-system approach combining the experimental advantages of Xenopus embryology and mouse genetics, has the potential to significantly advance our understanding of early lung development. Aim 1: Determine the mechanisms by which Osr1/2 transcription factors regulate the molecular pathway controlling Xenopus lung development. Aim 2: Test the hypothesis that Osr1 and Osr2 are required for lung development in mice.